The goal of this research program is to identify the mechanisms that allow hematopoietic stem cells (HSC) to differentiate into hepatocytes. The project detailed in this proposal is based on a mouse model for liver regeneration. Specifically we propose: 1) To test whether a single, highly purified HSC can differentiate into both the hematopoietic and hepatic lineage. 2) To conduct comparative studies between highly purified HSC from different sources with the aim of defining the best source of HSC for hepatic engraftment. 3) To examine whether hematopoietic engraftment is an obligatory step for hepatocyte differentiation. 4) Characterization of a transitional intermediate cell between HSC and hepatocytes. 5) To test whether HSC can contribute to other non-hematopoietic tissues. 6) To test whether human HSC can differentiate into hepatocytes. These discoveries together enable the identification of key factors for HSC plasticity. We propose that HSC-derived hepatocytes could be the basis for the development of cell-based therapeutics addressing a myriad of devastating human liver diseases.